EP3744723B1 - Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound - Google Patents

Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound Download PDF

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Publication number
EP3744723B1
EP3744723B1 EP19743399.8A EP19743399A EP3744723B1 EP 3744723 B1 EP3744723 B1 EP 3744723B1 EP 19743399 A EP19743399 A EP 19743399A EP 3744723 B1 EP3744723 B1 EP 3744723B1
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EP
European Patent Office
Prior art keywords
compound
formula
deuterium
hydrogen
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP19743399.8A
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German (de)
English (en)
French (fr)
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EP3744723A1 (en
EP3744723A4 (en
Inventor
Yihan Wang
Jiuyang ZHAO
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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Publication of EP3744723A1 publication Critical patent/EP3744723A1/en
Publication of EP3744723A4 publication Critical patent/EP3744723A4/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • TrkA receptors and TrkC receptors have been observed in the osteogenic region of the fractured mouse model. In addition, almost all osteoblast apoptosis agents are very advantageous. Expression of TrkA receptors and TrkC receptors has been observed in the osteogenic region of the fractured mouse model. In addition, localization of NGF was observed in almost all osteoblasts. Recently, it was demonstrated that pan-Trk inhibitors could inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors in human hFOB osteoblasts. This data support the theory of using Trk inhibitors to treat bone remodeling diseases, such as bone metastasis in cancer patients.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form the pharmaceutical composition.
  • the present disclosure discloses a compound of formula (A), or a pharmaceutically acceptable salt, a hydrate or a solvate, a polymorph, a stereoisomer or an isotopic variant thereof, wherein,
  • the compounds of formula (A), formula (A-1), formula (I) and formula (II) contain at least one deuterium atom, more preferably one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms, more preferably ten deuterium atoms, more preferably eleven deuterium atoms, more preferably twelve deuterium atoms, more preferably thirteen deuterium atoms, more preferably fourteen deuterium atoms, and more preferably fifteen deuterium atoms.
  • R 6 , R 7 and R 8 are all deuterium.
  • R 6 , R 7 and R 8 are all hydrogen.
  • the invention relates to a compound of formula (Aa), or a pharmaceutically acceptable salt, a hydrate or a solvate, a polymorph, or a stereoisomer thereof,
  • the present description discloses a compound of formula (Aa), formula (Aa-1), formula (Ia) and formula (IIa), wherein R 2 -R 5 and R 11 -R 12 are selected from hydrogen, R 1 and R 6 -R 10 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 , with the proviso that the above compound contains at least one deuterium.
  • the present description discloses a compound of formula (Aa), formula (Aa-1), formula (Ia) and formula (IIa), wherein R 2 -R 5 and R 9 -R 10 are selected from hydrogen, R 1 , R 6 -R 8 and R 11 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 , with the proviso that the above compound contains at least one deuterium.
  • the present description discloses a compound of formula (Aa), formula (Aa-1), formula (Ia) and formula (IIa), wherein R 1 and R 6 -R 8 are selected from deuterium, R 2 -R 5 and R 9 -R 10 are selected from hydrogen, R 11 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 .
  • the present description discloses a compound of formula (Aa), formula (Aa-1), formula (Ia) and formula (IIa), wherein R 1 and R 6 -R 8 are selected from deuterium, R 2 -R 5 are selected from hydrogen, R 9 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 .
  • the present description discloses a compound of formula (Aa), formula (Aa-1), formula (Ia) and formula (IIa), wherein R 1 and R 6 -R 8 are selected from deuterium, R 2 -R 5 and R 9 -R 10 are selected from hydrogen, R 11 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 .
  • a solid oral composition can be prepared by a conventional method of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules, to obtain the core of a tablet or dragee.
  • suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the additional therapeutic agents are selected from signal transduction pathway inhibitors, including, for example, Ras-Raf-MEK-ERK pathway inhibitors (e.g., sorafenib, trimetinib, or vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosine, or sirolimus) and modulators of the apoptotic pathway (e.g., obataclax).
  • Ras-Raf-MEK-ERK pathway inhibitors e.g., sorafenib, trimetinib, or vemurafenib
  • PI3K-Akt-mTOR-S6K pathway inhibitors e.g., everolimus, rapamycin, perifosine, or sirolimus
  • modulators of the apoptotic pathway e.g., obataclax
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 °C to 100 °C, preferably 0 °C to 80 °C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP19743399.8A 2018-01-23 2019-01-23 Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound Active EP3744723B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810063754 2018-01-23
PCT/CN2019/072833 WO2019144885A1 (zh) 2018-01-23 2019-01-23 取代的吡唑并[1,5-a]嘧啶类的大环化合物

Publications (3)

Publication Number Publication Date
EP3744723A1 EP3744723A1 (en) 2020-12-02
EP3744723A4 EP3744723A4 (en) 2021-05-19
EP3744723B1 true EP3744723B1 (en) 2023-10-18

Family

ID=65917013

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19743399.8A Active EP3744723B1 (en) 2018-01-23 2019-01-23 Substituted pyrazolo[1,5-a]pyrimidine macrocyclic compound

Country Status (5)

Country Link
US (1) US11345703B2 (zh)
EP (1) EP3744723B1 (zh)
JP (1) JP7162915B2 (zh)
CN (2) CN111848622A (zh)
WO (1) WO2019144885A1 (zh)

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* Cited by examiner, † Cited by third party
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WO2019144885A1 (zh) * 2018-01-23 2019-08-01 深圳市塔吉瑞生物医药有限公司 取代的吡唑并[1,5-a]嘧啶类的大环化合物
CN113490664A (zh) 2018-10-22 2021-10-08 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
WO2021027503A1 (zh) * 2019-08-12 2021-02-18 罗欣药业(上海)有限公司 三环类化合物、其制备方法、中间体及应用
CN113004305B (zh) * 2019-12-19 2024-04-09 赛诺哈勃药业（成都）有限公司 大环化合物及其制备方法和用途
CN111777549A (zh) * 2020-07-07 2020-10-16 中瀚(齐河县)生物医药科技有限公司 一种2-甲氧基-3-溴-5-氟吡啶的合成工艺
CN114230553B (zh) * 2020-09-09 2023-05-05 凯特立斯（深圳）科技有限公司 一种左旋烟碱的不对称合成方法
CN111875620B (zh) * 2020-09-28 2020-12-11 上海美迪西生物医药股份有限公司 吡唑并嘧啶类大环衍生物及其应用
WO2024017305A1 (zh) * 2022-07-20 2024-01-25 广州嘉越医药科技有限公司 含氰基取代的大环类化合物的用途

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Also Published As

Publication number Publication date
US11345703B2 (en) 2022-05-31
CN111848622A (zh) 2020-10-30
WO2019144885A1 (zh) 2019-08-01
CN109575025B (zh) 2020-09-11
EP3744723A1 (en) 2020-12-02
EP3744723A4 (en) 2021-05-19
JP7162915B2 (ja) 2022-10-31
US20210047330A1 (en) 2021-02-18
JP2021511353A (ja) 2021-05-06
CN109575025A (zh) 2019-04-05

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